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Melanoma Metastasized to the Brain and Steroids (MEMBRAINS)

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ClinicalTrials.gov Identifier: NCT03563729
Recruitment Status : Recruiting
First Posted : June 20, 2018
Last Update Posted : March 12, 2020
Sponsor:
Information provided by (Responsible Party):
Inge Marie Svane, Herlev Hospital

Study Description
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Brief Summary:
This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Patients will be treated in four arms depending on steroid dose level at inclusion (> 10 < 25 mg prednisolone or > 25 mg prednisolone) and treatment (pembrolizumab alone or the combination of ipilimumab and nivolumab).

Condition or disease Intervention/treatment Phase
Malignant Melanoma Drug: Pembrolizumab Injection [Keytruda] Drug: Ipilimumab Injection [Yervoy] Drug: Nivolumab Injection [Opdivo] Drug: Encorafenib Drug: Binimetinib Drug: Dabrafenib Drug: Trametinib Phase 2

Detailed Description:

Cancer immunotherapy with checkpoint inhibitors (CPI) has demonstrated significant response rates, with clinical responses of exceptional duration observed in pivotal clinical trials for multiple types of solid tumors. Results from clinical trials demonstrate a considerable survival benefit of CPI over standard treatments, leading to registration of CPI for lung-, head and neck-, bladder-, renal cancer, lymphomas and metastatic melanoma (MM). To date, CPI appear to hold the key for longterm survival - at least for patients treated in clinical trials.

Patients enrolled in pivotal clinical trials for immunotherapy of MM are highly selected and does not include patients with brain metastases. Small phase II studies lend support to CPI to yield responses in melanoma that has metastasized to the brain. However, a large proportion of patients that develop brain metastasis will require continued systemic treatment with steroids to alleviate symptoms from the central nervous system (CNS). This group of patients are not offered treatment with CPI, as it is generally assumed that steroid treatment hamper their clinical efficacy. Thus, this group of patients face a large unmet need.

Due to the immune inhibiting effects, steroids are used to manage immune-related adverse events (irAEs) induced by CPI treatment. However, patients receiving steroids in this context are still able to achieve and maintain clinical benefit even after stopping treatment.

It is not known whether steroid treatment at the time of initiation of CPI treatment diminishes the treatment effect, as patients in need of steroid treatment are generally excluded from clinical trials.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Six patients are enrolled in each arm. If clinical benefit is observed, each arm will be expanded to enroll a total of 20 patients.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy of Immunotherapy in Melanoma Patients With Brain Metastases Treated With Steroids
Actual Study Start Date : June 6, 2018
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 6, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: B: Pembrolizumab (Prednisolone >10 mg)
Intravenous infusion of pembrolizumab 2 mg/kg every third week for up to two years.
 Drug: Pembrolizumab Injection [Keytruda]
Alone
Experimental: C: Ipilimumab/nivolumab (Prednisolone 11-25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
 Drug: Ipilimumab Injection [Yervoy]
In combination with nivolumab.

Drug: Nivolumab Injection [Opdivo]
In combination with ipilimumab.
Experimental: D: Ipilimumab/nivolumab (Prednisolone >25 mg)
Intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
 Drug: Ipilimumab Injection [Yervoy]
In combination with nivolumab.

Drug: Nivolumab Injection [Opdivo]
In combination with ipilimumab.
Experimental: E: BRAF/MEK -> ipi/nivo (prednisolone >10 mg)
Induction treatment with BRAF/MEK inhibitors (either the combination of encorafenib/binimetinib or dabrafenib/trametinib) orally for 28 days followed by intravenous infusion of ipilimumab 3 mg/kg and nivolumab 1 mg/kg four times every three weeks in the induction phase and nivolumab 480 mg every four weeks in the maintenance phase for up to two years.
 Drug: Ipilimumab Injection [Yervoy]
In combination with nivolumab.

Drug: Nivolumab Injection [Opdivo]
In combination with ipilimumab.

Drug: Encorafenib
In combination with binimetinib

Drug: Binimetinib
In combination with encorafenib

Drug: Dabrafenib
In combination with dabrafenib

Drug: Trametinib
In combination with trametinib


Outcome Measures
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Primary Outcome Measures :
  1. 6 months progression-free survival rate [ Time Frame: 6 months ]
    Proportion of patients who did not progress or die within 6 months from commencing study treatment.

  2. 6 months overall survival rate [ Time Frame: 6 months ]
    Proportion of patients who did not die within 6 months from commencing study treatment.


Secondary Outcome Measures :
  1. Overall progression-free survival [ Time Frame: 4 years ]
    Time from commencing study treatment to the date of progression or death.

  2. Overall survival [ Time Frame: 4 years ]
    Time from commencing study treatment to the date of death from any cause.

  3. Overall response rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete or partial response according to modified RECIST 1.1.

  4. Extracranial response rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete or partial response in extracranial lesions according to modified RECIST 1.1.

  5. Intracranial response rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete or partial response in intracranial lesions according to modified RECIST 1.1.

  6. Intracranial clinical benefit rate [ Time Frame: 4 years ]
    Proportion of patients with an overall complete, partial response or stable disease > 6 months according to modified RECIST 1.1.

  7. Blood and tissue biomarkers of response and progression [ Time Frame: 5 years ]
    Correlation of the baseline PD-L1 status, immune markers, genomics and other biomarkers in tumour tissue and blood with complete or partial response and at subsequent disease progressionanalyses of potential specific biomarkers predictive of response or progression.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed metastatic melanoma with radiologically verified brain metastasis
  • Need for systemic steroid treatment (prednisolone > 10 mg daily; dexamethasone > 1.6 mg daily, hydrocortisone > 40 mg daily or equivalent) due to brain metastasis
  • At least one measurable lesion according to RECIST version 1.1 guidelines
  • Evaluable intracranial disease
  • 18 years of age or older
  • Performance status 0-2
  • Able to undergo MRI with gadolinium contrast agent
  • Adequate hematological and organ function
  • No significant toxicity from previous cancer treatments (CTC<1)
  • Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives
  • Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
  • Signed statement of consent after receiving oral and written study information.
  • Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.
  • For arm E specifically: Tumor cells must harbor BRAF mutation.

Exclusion Criteria:

  • Another malignancy or concurrent malignancy unless disease-free for 3 years
  • Ocular melanoma
  • Neurological symptoms from brain metastases present at baseline despite steroid treatment, unless symptoms are related to prior surgery
  • Known hypersensitivity to one of the active drugs or excipients
  • Acute or chronic infections with HIV or hepatitis
  • Any medical condition that will interfere with patient compliance or safety
  • Prior treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the metastatic setting
  • Prior systemic treatment with anti-PD-1/PD-L1/PD-L2/CTLA-4 antibodies in the adjuvant setting, unless completed more than 6 months before enrolment in this study
  • Simultaneous treatment with other experimental drugs or other anti-cancer drugs
  • Pregnant or breastfeeding females.
  • For arm E specifically: Prior treatment with BRAF/MEK inhibitors.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03563729


Contacts
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Contact: Inge M Svane, Professor 004538683868 inge.marie.svane@regionh.dk
Contact: Troels H Borch, PhD 004538683868 troels.holz.borch@regionh.dk

Locations
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Denmark
Herlev Universityhospital Recruiting
Herlev, Hovedstaden, Denmark, 2730
Contact: Inge M Svane, Professor    004538683868    inge.marie.svane@regionh.dk   
Contact: Troels H Borch, PhD    004538683868    troels.holz.borch@regionh.dk   
Principal Investigator: Troels H Borch, PhD         
Sub-Investigator: Marco Donia, PhD         
Aarhus Universityhospital Not yet recruiting
Aarhus, Midt, Denmark, 8000
Contact: Henrik Schmidt, PhD         
Principal Investigator: Henrik Schmidt, PhD         
Odense Universityhospital Not yet recruiting
Odense, Syd, Denmark, 5000
Contact: Lars Bastholt         
Principal Investigator: Lars Bastholt         
Sponsors and Collaborators
Inge Marie Svane
Investigators
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Principal Investigator: Troels H Borch, PhD Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology
More Information
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Additional Information:

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Responsible Party: Inge Marie Svane, Professor, MD, PhD, Herlev Hospital
ClinicalTrials.gov Identifier: NCT03563729    
Other Study ID Numbers: MM1807
First Posted: June 20, 2018    Key Record Dates
Last Update Posted: March 12, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Inge Marie Svane, Herlev Hospital:
Immune therapy
checkpoint inhibitor
pembrolizumab
ipilimumab
nivolumab
 steroid
brain metastasis
BRAF inhibitor
MEK inhibitor
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
 Nivolumab
Ipilimumab
Trametinib
Dabrafenib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action